Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in women of fertile age, affecting 5–10% of the female population. The syndrome is characterized by chronic anovulation, hyperandrogenism, polycystic ovaries, and decreased fertility 1. PCOS is a heterogeneous disorder that presents with a spectrum of symptoms and manifestations that vary over time. This leads to difficulties in diagnosing the syndrome. The diagnostic criteria for PCOS were revised at an International Expert Conference in Rotterdam in 2003 2 According to the Rotterdam criteria, diagnosis of PCOS requires at least two of the three following features 2.
- Clinical and/or biochemical hyperandrogenism.
- Polycystic ovaries on ultrasound.
PCOS is furthermore associated with insulin resistance, accumulation of abdominal fat, and obesity (BMI>30 kg/m2), which is present in ∼50% of women with PCOS 3,4.
It is well known that reproductive function in women with PCOS is strongly dependent on body weight and the metabolic status of the patient 5.
Considering the worldwide epidemic of obesity, clinical problems relating to PCOS may worsen and increase in frequency. Lifestyle interventions resulting in weight loss comprise the most successful strategy to improve symptoms of PCOS. However, many patients fail to lose weight or may quickly regain weight, which makes it unavoidable to face such a problem with PCO patients 6.
A large proportion of such patients will have to use assisted reproductive technologies such as IVF or intracytoplasmic sperm injection (ICSI) cycles. Our study will focus on the association between PCOS and obesity and how obesity will affect the outcome of ICSI cycles in obese women with PCOS.
Patients and methods
This is a retrospective study involving PCO patients who underwent ICSI cycles in IVF Unit, Kasr Al Ainy Hospital, Cairo University, Egypt during the period from March 2010 to June 2011. Eighty-one patients who fulfilled the inclusion criteria were recruited in the 15 months of study duration. Approval was obtained from the ethical committee of the unit.
Patients were enrolled in the study if they fulfilled the following criteria: age ranged from 20–38 years and they all have an ultrasound picture of PCO in one or both ovaries and undergoing their first ICSI cycles.
The weight and height of all patients in the study were registered and BMI was calculated by dividing the weight (in kilograms) by the square of the height (in meters) 6.
Patients were classified according to their BMI into two groups: the first group included 32 patients with BMI less than 30 kg/m2 and the second group included 49 patients with BMI more than 30 kg/m2.
All the patients included were undergoing ICSI cycles through the Long protocol in which the patients start the cycle of treatment by low dose oral contraceptive pills on day 4 of the preceding cycle; downregulation starts midluteal on day 20 of this cycle by daily subcutaneous injections of GNRH agonist Triptorelin (Decapeptyl 0.1; Ferring, Italy). Ovarian stimulation is started after the patient is being downregulated [as evidenced by endometrial thickness <5 mm and/or estradiol (E2) levels <50 pg/ml] on day 2 or 3 of her menstrual cycle by daily Human menopausal gonadotropins (HMG) intramuscular injection (Merional; IBSA, Boloanga, Switzerland). The starting dose of 150–225 IU was used according to the patient’s age, antral follicle count , basal follicle-stimulating hormone (FSH) level, and previous ovarian response. The first control (ultrasound and serum E2) was normally performed after 5 days of stimulation. Monitoring of follicular growth was achieved with serial ultrasound and serum E2 measurements and the dose of gonadotropins was adjusted, if necessary, according to follicular response. Triggering was established by HCG (Choriomon; IBSA) 5000–10 000 IU after ultrasound evidence of follicle maturity (when at least 3 follicles with size >18 mm).
Transvaginal ultrasound-directed oocyte retrieval was performed 35–36 h after triggering by HCG under general anesthesia.
Embryo transfer was performed on day 2 or 3 from the day of ovum pick-up. Number of embryos transferred was decided according to embryo quality day using soft transfer catheters. All patients received 400 mg natural progesterone vaginal suppositories (Prontogest 400 mg; IBSA) twice daily starting from the day of oocyte retrieval until negative pregnancy test or a viable fetus was documented by transvaginal sonography.
B-HCG level was assessed 14 days after the transfer, and the result is not regarded as being positive except for values exceeding 50 IU/l. Clinical pregnancy was defined as a positive serum β-HCG test result with ultrasound evidence of a gestational sac and fetal heart.
The primary outcome was to compare the outcome parameters of ICSI cycles in the two groups, including the number of oocytes retrieved, mature oocytes, fertilization rate, pregnancy rate, and the risk of developing ovarian hyperstimulation syndrome (OHSS).
The secondary outcome was to compare the demographic data and basal hormonal levels in the two studied groups, including basal FSH, luteinizing hormone (LH), E2, prolactin (PRL), and thyroid-stimulating hormone (TSH), in addition to comparing the total dose of HMG needed to establish the induction, which was calculated through multiplying the daily dose by number of days needed.
Statistic package for social sciences (SPSS, v 15.0 for Windows; SPSS Inc., Chicago, Illinois, USA) software was used for data analysis. Statistical significance was assessed using the Student t-test and the χ2-test as appropriate data were log-transformed to correct for skewness before statistical analysis, and values in the two groups were compared using the Mann–Whitney U-test. Significance was interpreted as P value less than 0.05. All data were presented as mean±SD.
Our results revealed nonsignificant difference between the two groups regarding the antral follicle count and basal hormonal levels of FSH and TSH. However, there were significantly higher levels of LH and PRL in the first group (nonobese patients) associated with significantly lower levels of basal E2 levels in the same group (Tables 1 and 2).
As for the total dose of induction, there was no significant difference between obese and nonobese PCO patients. Similarly, there was no difference in the number of oocytes retrieved in the two groups. However, there was a significantly higher number of mature oocytes in the obese group associated with a higher rate of fertilization that represented a significant difference between the two groups.
Regarding the pregnancy rate and the subsequent development of moderate to severe OHSS, no difference was found between obese and nonobese PCO patients.
In this study, we are trying to study the effect of obesity (represented by BMI) on PCO patients undergoing ICSI cycles and to what extent would increased body fatness and increased BMI change the expected outcome after ICSI cycles treatment.
We conducted our study on 81 patients, all of them showing ultrasound picture of PCO with little respect to the rest of the criteria needed to complete the diagnosis of PCO syndrome, as both groups show the same response in ICSI cycles, the point which was stated by Esinler et al. 7 who conducted their study on 99 consecutive infertile women (n=109 cycles) with PCOS and 58 patients (n=58 cycles) with isolated PCO morphology undergoing ICSI cycles in the IVF Center of Hacettepe University, Faculty of Medicine. They prospectively analyzed their data regarding the oocyte number, fertilization rate, embryo quality, clinical pregnancy rate, implantation rate, and OHSS, then they came out with results showing that patients with the full-blown picture of PCOS or isolated PCO-only morphology behave exactly in the same manner during all stages of assisted reproduction, a conclusion that was also obtained by Swanton et al.8 in their research about the same object.
Analysis of our data revealed significant higher basal levels of LH in the nonobese group with BMI less than 30 compared with the obese patients with BMI more than 30 (P=0.0001 and 0.006, respectively). This is in agreement with the study by Pagan et al.9 who studied 24 women with PCOS across a spectrum of BMIs with frequent blood sampling, intravenous administration of GnRH (75 ng/kg), and subcutaneous administration of the NAL-GLU GnRH antagonist (5 μg/kg) in the General Clinical Research Center at an academic hospital, coming out with results that illustrate the inverse correlation between BMI and mean LH, LH/FSH, and LH pulse amplitude. They also suggested that the effect of BMI on LH is mediated at a pituitary and not a hypothalamic level in PCOS, as they noticed that the pituitary response to a weight-based dose of GnRH is inversely related to BMI in PCOS.
This conclusion was also obtained by Bohlke et al.10 who assessed the relationship between BMI and basal LH and the LH–FSH ratio revealing the same inverse association between BMI and basal LH levels, but the study was on normally menstruating women and not on PCO patients.
However, in contrast, Sathya et al.11 and Hill et al.12, who studied the impact of BMI on the outcome of ICSI cycles (they classified their patients only according to their BMI without focusing on PCO patients), have stated in their results that the level of basal LH did not differ between obese and lean women.
Our results also revealed significantly lower levels of prolactin and higher levels of E2 in the obese group compared with the nonobese candidates. This finding is also an important secondary outcome observed in this study. As regards the total dose needed for induction in the two studied groups, results revealed no significant difference.
This finding does not agree with the outcome obtained by Ozgun et al.13 after studying the ICSI results of 46 patients with PCOS who underwent the long protocol pituitary suppression, ovarian stimulation, and ICSI with fresh embryo transfer. They found that obese patients (BMI≥30 kg/m2) required higher doses of gonadotropin (2994 vs. 1719 IU; P<0.001) when compared with the nonobese ones (BMI<30 kg/m2); in addition, similar finding was reached to by Fedorcsák et al.14.
As for the expected outcome, no significant difference was observed in the number of retrieved oocytes, but there were more mature oocytes (P=0.03) and higher fertilization rate (P=0.001) in the obese patients (BMI≥30 kg/m2) that reached to be significant when compared with the other nonobese patients.
This finding can be explained by the higher levels of basal LH observed in the nonobese PCO group, a fact that was found to be associated with lower fertilization rates as stated by Esmailzadeh et al.15 who examined the demographic characteristics of 315 women with medical indication for conventional IVF treatment to determine the predictors of clinical fertilization in IVF cycles where the mean of basal LH serum on day 2 was a negative predictor of fertilization.
Other authors have also recorded that obese PCO patients produce less oocytes after ovulation superstimulation for IVF or ICSI cycles, such as McCormick et al.16 who carried out a retrospective analysis on the data of 94 fresh nondonor IVF-embryo transfer cycles to conclude that lean PCOS patients used fewer gonadotropin ampules (18.8±6.0 vs. 29.2±14.2) and had more retrieved oocytes (22.2±9.2 vs. 14.3±4.9) than obese PCOS patients.
Finally, what is most important is that there was no significant difference in the pregnancy rate or the rate of developing moderate to severe OHSS between the obese and nonobese candidates. This primary outcome agrees with the outcome of McCormick et al.16. In their study, it was made well clear that, although nonobese patients showed favorable IVF criteria, there was no significant difference in outcome compared with the obese group. It should also be noted that the miscarriage rate was not evaluated in this current study. Ozgun et al.13 reported that the miscarriage rate was significantly higher in obese PCOS. At this particular point, weight reduction in PCOS is still considered to optimize ICSI outcome.
According to this study, we can conclude that despite the health hazards of obesity that are well known and proven, obese PCO patients are not expected to produce a worse IVF outcome as regards to the pregnancy rate and occurrence of severe OHSS. Yet, weight reduction before ICSI is still to be considered as it may reduce the miscarriage rate. Finally, we should also emphasize that these important findings need further studies on larger numbers of candidates to have a clear widely accepted result, and hence develop well-defined guidelines and recommendations.
Conflicts of interest
There are no conflicts of interest.
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